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A selective α 2 B adrenoceptor agonist (A‐1262543) and duloxetine modulate nociceptive neurones in the medial prefrontal cortex, but not in the spinal cord of neuropathic rats
Author(s) -
Chu K.L.,
Xu J.,
Frost J.,
Li L.,
Gomez E.,
Dart M.J.,
Jarvis M.F.,
Meyer M.D.,
McGaraughty S.
Publication year - 2015
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.586
Subject(s) - duloxetine , agonist , nociception , prefrontal cortex , spinal cord , neuroscience , chemistry , receptor , endocrinology , pharmacology , medicine , psychology , pathology , alternative medicine , cognition
Background The noradrenergic system contributes to pain modulation, but the roles of its specific adrenoceptors are still being defined. We have identified a novel, potent (rat EC 50 = 4.3 nM) and selective α 2B receptor agonist, A ‐1262543, to further explore this adrenoceptor subtype's contribution to pathological nociception. Methods Systemic administration of A ‐1262543 (1–10 mg/kg, intraperitoneal) dose‐dependently attenuated mechanical allodynia in animals with a spinal nerve ligation injury. To further explore its mechanism of action, the activity of nociceptive neurones in the spinal cord and medial prefrontal cortex ( mPFC ) were examined after injection of 3 mg/kg of A ‐1262543 (intravenous, i.v.). These effects were compared with duloxetine (3 mg/kg, i.v.), a dual noradrenaline ( NA ) and serotonin (5‐ HT ) reuptake inhibitor. Results Systemic administration of A ‐1262543 or duloxetine did not alter the spontaneous or evoked firing of spinal wide dynamic range and nociceptive‐specific neurones in the neuropathic rats, indicating that neither compound engaged spinal, peripheral or descending pathways. In contrast to the lack of effect on spinal neurones, both A ‐1262543 and duloxetine reduced the evoked and spontaneous firing of ‘pain‐responsive’ ( PR ) neurones in the mPFC . Duloxetine, but not A ‐1262543, also inhibited the firing of pain non‐responsive ( nPR ) neurones in the mPFC probably reflecting duloxetine's contribution to modulating non‐pain endpoints. Conclusions These data highlight that activation of the α 2B adrenoceptor as well as inhibiting NA and 5‐ HT reuptake can result in modulating the ascending nociceptive system, and in particular, dampening the firing of PR neurones in the mPFC .